Determination of Relative Weightings for Sacroiliac Joint Pathologies in the OMERACT Juvenile Arthritis Magnetic Resonance Imaging Sacroiliac Joint Score.

This study aims to determine the relative weights (point value) of items of the juvenile idiopathic arthritis magnetic resonance imaging-sacroiliac joint scoring system (JAMRIS-SIJ). An adaptive multicriteria decision analysis was performed using the 1000Minds web application to determine the relative weights of the items in the JAMRIS-SIJ inflammation and damage domains. Experts in imaging and rheumatology independently completed a conjoint analysis survey (CAS) to determine the point value of the measurement items of the JAMRIS-SIJ. Each CAS survey question asked the expert to compare two hypothetical patient profiles, which were otherwise similar but different at two items at a time, and to select which item showed a more severe stage of inflammation or osteochondral damage. In addition, experts ranked 14 JAMRIS-SIJ grade only or image + grade patient vignettes while blinded to the CAS-derived weights. The validity of the weighted JAMRIS-SIJ was tested by comparing the expert CAS-weighted score and the image + grade ranking method. Seventeen experts completed the CAS (11 radiologists and 6 rheumatologists). Considering the point value for inflammation domain items, osteitis (24.7%) and bone marrow edema (24.3%) had higher group-averaged percentage weights compared to inflammation in erosion cavity (16.9%), joint space enhancement (13.1%), joint space fluid (9.1%), capsulitis (7.3%), and enthesitis (4.6%). Similarly, concerning the damage domain, ankylosis (41.3%) and erosion (25.1%) showed higher group-averaged weights compared to backfill (13.9%), sclerosis (10.7%), and fat metaplasia lesion (9.1%). The Spearman correlation coefficients of the CAS-weighted vignette order and unweighted JAMRIS-SIJ grade only order vignettes for all experts were 0.79 for inflammation and 0.80 for damage. The correlations of image vignettes among imaging experts to CAS were 0.75 for inflammation and 0.90 for damage. The multicriteria decision analysis identified differences in relative weights among the JAMRIS-SIJ measurement items. The determination of the relative weights provided expert-driven score scaling and face validity for the JAMRIS-SIJ, enabling the future evaluation of its longitudinal construct validity.

Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial.

OBJECTIVE: This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA). METHODS: In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0-16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16-48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety. RESULTS: Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA. CONCLUSION: Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred. CLINICAL TRIAL REGISTRATION: NCT01230827; Results.

Toward Establishing a Standardized Magnetic Resonance Imaging Scoring System for Temporomandibular Joints in Juvenile Idiopathic Arthritis.

OBJECTIVE: The temporomandibular joints (TMJs) are frequently affected in children with juvenile idiopathic arthritis (JIA). Early detection is challenging, as major variation is present in scoring TMJ pathology on magnetic resonance imaging (MRI). Consensus-driven development and validation of an MRI scoring system for TMJs has important clinical utility in timely improvement of diagnosis and serving as an outcome measure. We report on a multi-institutional collaboration toward developing a TMJ MRI scoring system for JIA. METHODS: Seven readers independently assessed MRI scans from 21 patients (42 TMJs, from patients ages 6-16 years) using 3 existing MRI scoring systems from American, German, and Swiss institutions. Reliability scores, scoring system definitions, and items were discussed among 10 JIA experts through 2 rounds of Delphi surveys, nominal group voting, and subsequent consensus meetings to create a novel TMJ MRI scoring system. RESULTS: Average-measure absolute agreement intraclass correlation coefficients (avICCs) for the total scores of all 3 scoring systems were highly reliable at 0.96 each. Osteochondral items showed higher reliability than inflammatory items. An additive system was deemed preferable for assessing minor joint changes over time. Eight items were considered sufficiently reliable and/or important for integration into the consensus scoring system: bone marrow edema and enhancement (avICC 0.57-0.61, smallest detectable difference [SDD] ± 45-63% prior to redefining), condylar flattening (avICC 0.95-0.96, SDD ± 23-28%), effusions (avICC 0.85-0.88, SDD ± 25-26%), erosions (avICC 0.94, SDD ± 20%), synovial enhancement and thickening (previously combined, avICC 0.90-0.91, SDD ± 33%), and disk abnormalities (avICC 0.90, SDD ± 19%). CONCLUSION: A novel TMJ MRI scoring system was developed by consensus. Further iterative refinements and reliability testing are warranted in upcoming studies.

Magnetic Resonance Imaging (MRI) of the Knee as an Outcome Measure in Juvenile Idiopathic Arthritis: An OMERACT Reliability Study on MRI Scales.

OBJECTIVE: There is increasing evidence that early therapeutic intervention improves longterm joint outcome in juvenile idiopathic arthritis (JIA). Given the existence of highly effective treatments, there is an urgent need for reliable and accurate measures of disease activity and joint damage in JIA. Our objective was to assess the reliability of 2 magnetic resonance imaging (MRI) scoring methods: the Juvenile Arthritis MRI Scoring (JAMRIS) system and the International Prophylaxis Study Group (IPSG) consensus score, for evaluating disease status of the knee in patients with JIA. METHODS: Four international readers independently scored an MRI dataset of 25 JIA patients with clinical knee involvement. Synovial thickening, joint effusion, bone marrow changes, cartilage lesions, bone erosions, and subchondral cysts were scored using the JAMRIS and IPSG systems. Further, synovial enhancement, infrapatellar fat pad heterogeneity, tendinopathy, and enthesopathy were scored. Interreader reliability was analyzed by using the generalized κ, ICC, and the smallest detectable difference (SDD). RESULTS: ICC regarding interreader reliability ranged from 0.33 (95% CI 0.12-0.52, SDD = 0.29) for enthesopathy up to 0.95 (95% CI 0.92-0.97, SDD = 3.19) for synovial thickening. Good interreader reliability was found concerning joint effusion (ICC 0.93, 95% CI 0.89-0.95, SDD = 0.51), synovial enhancement (ICC 0.90, 95% CI 0.85-0.94, SDD = 9.85), and bone marrow changes (ICC 0.87, 95% CI 0.80-0.92, SDD = 10.94). Moderate to substantial reliability was found concerning cartilage lesions and bone erosions (ICC 0.55-0.72, SDD 1.41-13.65). CONCLUSION: The preliminary results are promising for most of the scored JAMRIS and IPSG items. However, further refinement of the scoring system is warranted for unsatisfactorily reliable items such as bone erosions, cartilage lesions, and enthesopathy.

Results of a multinational survey regarding the diagnosis and treatment of temporomandibular joint involvement in juvenile idiopathic arthritis.

BACKGROUND: Temporomandibular joint (TMJ) involvement occurs in up to 80% of patients with juvenile idiopathic arthritis (JIA). Currently there are no standardized procedures regarding diagnosis and treatment of this common complication of JIA. The aim of the study was to assess the current clinical practices in many countries regarding diagnosis and treatment of TMJ involvement in JIA. Pediatric rheumatologists were asked to fill out a survey with 8 items regarding diagnosis and treatment of TMJ involvement. The survey was distributed over the worldwide pediatric rheumatology electronic list-serve. Data was collected in an Excel spread sheet and analyzed using Excel software. FINDINGS: Eighty-seven centers responded to the survey between December 2009 and April 2010. All responding centers were actively screening for TMJ involvement. All centers were screening by physical exam, 85 (97%) by history, and 2 (3%) by imaging. Seventy-seven (88%) centers were screening at the first visit and 76 (87%) at each follow-up visit. If imaging was requested, 77% of the centers reported that they asked for MRI, 10% for ultrasound, 9% for CT and 33% for X-ray. The first line treatment of TMJ arthritis was a non-biologic DMARD in 36%, an NSAID in 33%, an intraarticular corticosteroid injection in 26%, and an anti-TNF agent in 5%. Overall, 57 (65%) of the centers were using intraarticular corticosteroid injections as treatment. CONCLUSIONS: TMJ arthritis is common among children with JIA. This survey shows that a wide array of diagnostic and therapeutic approaches is being employed for TMJ disease in 87 international centers. Due to this lack of agreement in how to diagnose and treat this JIA complication, we believe that an expert opinion/consensus statement regarding TMJ arthritis in JIA will likely benefit patients worldwide.

Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation.

Human multipotent mesenchymal stromal cells (MSCs) are clinically applied to treat autoimmune diseases and graft-versus-host disease due to their immunomodulatory properties. Several molecules have been identified to mediate these effects, including constitutively expressed galectin-1. However, there are indications in the literature that MSCs exert enhanced immunosuppressive functions after interaction with an inflammatory environment. Therefore, we analyzed how inflammatory stimuli influence the expression of the galectin network in MSCs and functionally tested the relevance for the immunomodulatory effects of MSCs. We found that galectin-9 was strongly induced in MSCs upon interaction with activated PBMCs. Proinflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), and also ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs. Galectin-9 was not only upregulated intracellularly, but also released by MSCs in significant amounts into the supernatant after exposure to proinflammatory stimuli. In proliferation assays, MSCs with a galectin-9 knockdown lost a significant portion of their antiproliferative effects on T cells. In conclusion, we found that unlike constitutively expressed galectin-1, galectin-9 is induced by several proinflammatory stimuli and released by MSCs. Thus, galectin-9 contributes to the inducible immunomodulatory functions of MSCs.

Patients with arthritis undergoing surgery: how should we manage tumour necrosis factor blocking agents perioperatively?-A systematic literature review.

We systematically reviewed the literature on the infectious risk in patients treated with tumour necrosis factor blocking agents (TNF-BA) undergoing surgery: we searched the Medline (PubMed) and the online archive from the Annual European Congress of Rheumatology and the Annual Scientific Meeting of the American College of Rheumatology. Of total 1259 reports, 14 were finally analysed. With one exception all were retrospective. Four of 6 studies compared patients on TNF-BA with those not receiving TNF-BA, and found an increased risk of infection with the use of TNF-BA. None of the other studies which compared continued with discontinued treatment at surgery found an increased risk of infection, when the medication was continued perioperatively. In conclusion, while in theory there is an increased risk of infections when TNF-BA are administered perioperatively, the available literature does not necessarily support this. It rather appears that patients receiving TNF-BA are a priori at a higher risk of postoperative infections. Scheduling surgery at the end of the drug interval and adding one "safety" week prior to surgery should be an acceptable plan in daily clinical practice.

Management of temporomandibular joint arthritis in adult rheumatology practices: a survey of adult rheumatologists.

BACKGROUND: The temporomandibular (TMJ) is frequently involved in juvenile idiopathic arthritis (JIA), however little is known about management of this joint once a patient transitions from pediatric to adult care and about how rheumatologists approach TMJ involvement in rheumatoid arthritis (RA). The objective of this project was to describe adult rheumatologists' approaches to the diagnosis and treatment of TMJ arthritis in adults with JIA or RA. FINDINGS: One hundred and eighteen rheumatologists responded to an online survey of adult rheumatologists in the United States and Canada. Respondents estimated that 1-25% of their patients with RA or JIA had TMJ arthritis. Respondents reported lower rates of MRI use (19%) and higher rates of use of splinting/functional devices (50%) than anticipated. Approximately 80% of respondents reported that their practice had a standardized approach to the evaluation of patients with TMJ arthritis. The most commonly used medical therapies were non-steroid anti-inflammatory drugs, anti-tumor necrosis factor alpha medications, and methotrexate. CONCLUSIONS: Despite the majority of respondents stating that their practices had a standardized approach to the diagnosis and treatment of TMJ disease, there nevertheless appeared to be a range of practices reported. Standardizing the evaluation and treatment of TMJ arthritis across practices may benefit both adult and pediatric patients.

Magnetic resonance imaging-guided osseous biopsy in children with chronic recurrent multifocal osteomyelitis.

PURPOSE: To report the safety and diagnostic performance of magnetic resonance (MRI)--guided core biopsy of osseous lesions in children with chronic recurrent multifocal osteomyelitis (CRMO) that were visible on MRI but were occult on radiography and computed tomography (CT). MATERIALS AND METHODS: A retrospective analysis of MRI-guided osseous biopsy performed in seven children (four girls and three boys; mean age 13 years (range 11 to 14) with CRMO was performed. Indication for using MRI guidance was visibility of lesions by MRI only. MRI-guided procedures were performed with 0.2-Tesla (Magnetom Concerto; Siemens, Erlangen, Germany; n = 5) or 1.5-T (Magnetom Espree; Siemens; n = 2) open MRI systems. Core needle biopsy was obtained using an MRI-compatible 4-mm drill system. Conscious sedation or general anesthesia was used. Parameters evaluated were lesion visibility, technical success, procedure time, complications and microbiology, cytology, and histopathology findings. RESULTS: Seven of seven (100%) targeted lesions were successfully visualized and sampled. All obtained specimens were sufficient for histopathological analysis. Length of time of the procedures was 77 min (range 64 to 107). No complications occurred. Histopathology showed no evidence of malignancy, which was confirmed at mean follow-up of 50 months (range 28 to 78). Chronic nonspecific inflammation characteristic for CRMO was present in four of seven (58%) patients, and edema with no inflammatory cells was found in three of seven (42%) patients. There was no evidence of infection in any patient. CONCLUSION: MRI-guided osseous biopsy is a safe and accurate technique for the diagnosis of pediatric CRMO lesions that are visible on MRI only.

NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment.

INTRODUCTION: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. METHODS: A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. RESULTS: All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. CONCLUSION: The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

Whole-body MRI: a helpful diagnostic tool for juvenile dermatomyositis case report and review of the literature.

Juvenile Dermatomyositis (JDM) is a rare autoimmune disease in childhood. Distinction between muscle inflammation and a residual state can be difficult especially under immunosuppressive therapy and in active disease without correlating muscle enzyme tests or functional muscle scores. Our goal is to demonstrate the benefit of whole-body magnetic resonance imaging (MRI) as a diagnostic modality in the detection and management of JDM. One patient with JDM was monitored using clinical examination, muscle enzyme tests, muscle scores and whole-body MRI. During immunosuppression, the patient presented several times to our department without clear correlation between clinical picture, muscle enzyme tests and muscle scores. Whole-body MRI proved reliable in assessing the true state of the disease, thus providing invaluable information in the management of the inflammatory myopathy. This is of utmost importance for the therapeutic optimization in order to prevent further damage especially in children with active but subclinical disease.

Rituximab for the treatment of refractory pediatric autoimmune diseases: a case series.

INTRODUCTION: To report on efficacy, tolerability and safety of rituximab in children with refractory autoimmune diseases. CASE PRESENTATION: Five patients (juvenile dermatomyositis, Wegener's granulomatosis, systemic lupus erythematosus, myasthenia gravis and multiple sclerosis with systemic lupus erythematosus) were treated with rituximab and followed for a median time of 2.5 years. Two patients achieved remission (systemic lupus erythematosus, Wegener's granulomatosis). Three patients had a refractory disease course and underwent autologous stem cell transplantation. Of those, two achieved remission (juvenile dermatomyositis, myasthenia gravis), one died of complications after transplantation (multiple sclerosis/systemic lupus erythematosus). No severe adverse events occurred. CONCLUSION: Efficacy of rituximab was variable ranging from complete remission to inefficacy. Treatment was safe.

Mesenchymal stromal cells: a novel treatment option for steroid-induced avascular osteonecrosis.

Mesenchymal stromal cells are multipotent cells capable of tissue repair and immune modulation. They are primarily found in bone marrow, but are also present in other tissues of mesenchymal origin, such as fatty tissue, muscle, tendons, etc. MSC can easily be obtained by bone marrow aspiration, showing a rapid expansion in vitro. New protocols enable cell culture without the use of animal-derived sera and artificial growth factors. Avascular necroses of the bone may have different causes. AVN in autoimmune and hematological diseases show a strong association with corticosteroid treatment, which is often unavoidable in severe cases. Until recently, core decompression of the affected osseous area was the standard approach. Because of their differentiation properties, easy accessibility and proliferative capacity, autologous MSCs could potentially complement AVN treatment by adding fresh "osteogenic cells" to the healing process.